This invention relates to compounds and compositions.
In a particular instance, the present invention relate to analgesia, methods of analgesia and analgesic compositions.
The present invention provides:
the new use of compounds of Formula II as shown in the accompanying drawings wherein
R1 is H or Me, preferably H;
R2 is OH, preferably in alpha conformation;
R3 is H;
or R2 and R3, taken together, are O;
R4 is H or Me, preferably Me and preferably in alpha conformation;
R5 and R6, taken together, are O;
R7 is H or Me, preferably H;
R8=H, OH, OAc, SH, SAc, Cl, Br, F
including solvates thereof, pharmaceutically acceptable derivatives thereof, prodrugs thereof, tautomers thereof, isomers thereof, and metabolites thereof.
The present invention also provides a method of analgesia comprising administering an effective amount of a compound of Formula II, wherein
R1 is H or Me, preferably H;
R2 is OH, preferably in alpha conformation;
R3 is H;
or R2 and R3, taken together, are O;
R4 is H or Me, preferably Me and preferably in alpha conformation;
R5 and R6, taken together, are O;
R7 is H or Me, preferably H;
R8=H, OH, OAc, SH, SAc, Cl, Br, F
including solvates thereof, pharmaceutically acceptable derivatives thereof, prodrugs thereof, tautomers thereof, isomers thereof, and metabolites thereof.
The present invention also provides an analgesic composition comprising a compound of Formula II, wherein
R1 is H or Me, preferably H;
R2 is OH, preferably in alpha conformation;
R3 is H;
or R2 and R3, taken together, are O;
R4 is H or Me, preferably Me and preferably in alpha conformation;
R5 and R6, taken together, are O;
R7 is H or Me, preferably H;
R8=H, OH, OAc, SH, SAc, Cl, Br, F
including solvates thereof, pharmaceutically acceptable derivatives thereof, prodrugs thereof, tautomers thereof, isomers thereof, and metabolites, thereof
We have found unexpectedly that metabolites and prodrugs of compounds of Formula II are also active as analgesic agents. Therefore the invention further comprises a composition when used as an analgesic comprising a metabolite or a prodrug of a compound of Formula II wherein
R1 is H or Me, preferably H;
R2 is OH, preferably in the alpha conformation
R3 is H
or R2 and R3, taken together, are O;
R4 is H or Me and preferably in the alpha conformation
R5 and R6, taken together, are O;
R7 is H or Me, preferably R;
R8=H, OH, Oac, SH, SAc, Cl, Cr, F.
In a further aspect of the invention there is disclosed a method of analgesia comprising administering an effective amount of a metabolite or a prodrug of a compound of Formula II wherein
R1 is H or Me, preferably H;
R2 is OH, preferably in the alpha conformation
R3is H
or R2 and R3, taken together, are O;
R4 is H or Me and preferably in the alpha conformation
R5 and R6, taken together, are O;
R7 is H or Me, preferably H;
R8=H, OH, Oac, SH, SAc, Cl, Cr, F.
The compounds of the invention are related to pregnane-dione which is shown in Formula I.
The following Patent Specifications describe some of the compounds and their method of preparation:
British Patent Specification No. 1,317,185 (Application No. 33162/72 filed May 16, 1973) to GLAXO;
German Patent Specification No. 2,255,108 (based on British Application No. 52465/71 filed Nov. 11, 1971) to GLAXO;
U.S. Pat. No. 3,558,608 (granted Jan. 27, 1971, filed Dec. 30, 1968) to SEARLE;
South African Patent Specification 70/03861 (filed Jan. 15, 1971 based on British Application filed Jun. 20, 1969) to GLAXO;
German Patent Specification No. 2,162,554 (filed Jun. 29, 1972, based on British Application No. 60,068/70 filed Dec. 17, 1970) to GEAXRO;
French Patent Specification No. 2,1187121 (filed Sep. 1, 1972, based on British Application 60,068/70 filed Dec. 17, 1970) to GLAXO and
German Patent Specification No. 2,162,593 (filed Jul. 6, 1972, based on British Application No. 60,067/70 filed Dec. 17, 1970) to GLAXO.
The whole of the subject matter of those specifications together with items 105627c and 9285v of Chemical Abstracts, Vol. 77, 1972; 64113v, 64114w, 20793n of Chemical Abstract 5, Vol. 75, 1971; 115783f and 66672h of Chemical Abstracts Vol 79, 1973; and 1020345 of Chemical Abstracts Vol 78, 1973 is to be considered included and imported hereinto.
A preferred compound for use is
21-acetoxy-3alpha-hydroxy-5alpha-pregnane-11,20-dione which is of Formula III and which is commonly referred to as alphadolone acetate.
Further preferred compounds of the invention include metabolites of alphadolone acetate.
More preferably a compound for use in the invention is alphadolone glucuronide.
The compounds may be used individually or in mixtures with other compounds or metabolites/prodrugs of compounds of Formula II.
In addition, compounds and metabolites of Formula II may be used concurrently with other analgesic drugs such as opioids to potentiate or increase the analgesic effects of those drugs. Suitable opioids for this use include morphine.
The compounds for use in this invention may be provided free acid form or as a salt. It is preferred that the compounds are provided as either sulphate or methane sulphonate salts.
The compositions of this invention may be prepared for administration by various routes including intravenous, intramuscular, peritoneal and any other convenient route. However, the applicant has found that effective results are obtained when a compound of Formula II is administered into the intestines particularly intragastically, and in a particular instance via an oral route.
Accordingly, in a preferred aspect, the present invention provides a composition in a form suitable for oral administration.
That form may include tablet, capsule or lozenge or a liquid form.
It is preferred that the composition contains a surfactant and/or a solubility improver. One solubility improver is water-soluble polyoxyethylated castor oil.
A suitable surfactant is Cremophor EL.
A suitable dosage in a 70 kg human would be about a maximum of 2.00 grams of the compound of Formula II every 6 hours.
We have conducted further scientific trials (see Examples 2 to 5) which provides evidence indicating that metabolites of alphadolone produced in the liver are responsible for the pain relieving effect of alphadolone when given orally and intraperitoneally to rats and orally to man. We have therefore prepared the following detailed description of such further evidence which we have obtained from our experimental data shown in Examples 2 to 5.
Alphadolone has been marketed as an anaesthetic (Saffan; Althesin) formulated in combination with another neurosteroid called alphaxalone. It is generally accepted in the literature that both alphaxalone and alphadolone are intravenous anaesthetics, i.e. when they are given intravenously, they produce sedation and unconsciousness to a level sufficient for surgery. Since the basis of our claim for the analgesic properties of alphadolone is that it does not produce sedation and unconsciousness when given as described in the patent, we though it important to investigate whether alphadolone on its own does have anaesthetic properties. Such data, although alluded to in the literature, is not stated clearly with scientific evidence. Thus, we performed the experiments described in Example 2. Rats were given an intravenous injection of alphadolone. All of the rats became unconscious and surgically anaesthetised within 5 seconds of the intravenous injection. The dose given intravenously would be expected to achieve blood levels very similar to a blood level that might be achieved after intraperitoneal injection of the dose of alphadolone used for anaesthesia in combination with alphaxalone. Thus, it can be concluded that intravenous injection of alphadolone produces unconsciousness. However, alphadolone given by other routes does not produce unconsciousness (vide infra).
Experiments with orally administered alphadolone are shown in Example 3 where. We have given a range of doses of alphadolone intragatrically to rats. Given by this route, alphadolone caused no sedation, even at very large doses. However, when the drug was given by this route, powerful antinociception (pain relief) occurred and this was due to an action of the drug or perhaps a metabolite on spinal cord receptors for the neurotransmitter gamma-aminobutyric acid (GABA). These, along with the results of experiments with intraperitoneal injections of alphadolone (Example 4 vide infra) encompass the essence of our discovery and invention, ie. the administration of a drug by a non-spinal route which produces pain relief by a selective action on spinal cord systems. Thus, pain relief is produced without alteration of conscious level, an extremely important property for a drug to be used as a pain reliever. That the drug does not have sedative properties when given intragastrically whereas it does when given intravenously implies that the body somehow alters the drug when given by this route. When a drug is absorbed from the stomach and intestine, the molecule is first presented to the liver in the body. One of the many functions of the liver is to metbolise compounds coming from the intestine. This may well have happened to the absorbed alphadolone to produce a metabolite which caused the effect. Since these data are included in our original patent application, we would say that the involvement of metabolites is implicit within these results, However, these results are supported further by subsequent experiments.
Experiments with intrapentoneal injections of alphadolone are shown in Example 4. Intrapentoneal injections of Saffan, the anaesthetic combination of alphaxalone and alphadolone produces unconsciousness to the state of surgical anaesthesia and subsequent sedation. However, after the sedation has completely worn off, there is revealed an antinociceptive (analgesic or pain relieving) effect. The experiments described in this document show that all of the sedative and anaesthetic properties of Saffan are due to its alphaxalone content when this combination is given intraperitoncally whereas the subsequent antinociceptive effects are totally due to the alphadolone content. By that we mean, when a dose of alphaxcalone is given, which is the same as the dose of alphaxalone given when the Saffan injection is administered, the same amount of anaesthesia and sedation is produced by the alphaxalone when given alone as is achieved with the Saffan. However, when the same dose of alphadolone is given alone that was administered in combination with alphaxalone in the Saffan injection, no sedation at all was produced but all of the antinociceptive effect was seen. Again, these results support the observations with the oral administration of alphadolone, i.e. that this drug does not produce any sedation when given by a route, which first presents the drug after absorption to the liver. It is likely therefore, that presentation of the alphadolone molecule to the liver prior to absorption into the rest of the body, inactivates the anaesthetic properties and activates the pain relieving properties; further evidence suggesting the involvement of metabolism and metabolites.
The experiments from our laboratory are supported by observations by an independent body, PAN LABS. A sample of alphadolone used in the above experiments in rats in our laboratory was sent to a commercial drug-testing house, called PAN LABS. They gave the drug to a number of preparations to look for toxicity effects as well as pharmacological effect. In one toxicity test performed at PAN LABS, doses of up to 300 mg per kg of alphadolone was given to mice. It was found that that dose did not produce anaesthesia, but merely a slight decrease in grip strengthxe2x80x94the ability of the animal to hang on to a rod tightly with its forepaws whilst being pulled away from the rod.
Thus all of the above suggest that alphadolone and it""s acetate salt are anaesthetics when given intravenously. However, when the drug is given by a route which first presents the drug to the liver after absorption prior to gaining access to the rest of the body, the drug is somehow modified to destroy its anaesthetic and sedative potency, but simultaneously to activate it""s analgesic effects. These observations are supported by experiments in humans (Example 5).
Experiments in humans conducted in Example 5 reports a Phase I/II study of oral administration of alphadolone in humans. The first pet of the study was a dose escalation study to assess safety. Doses up to 500 mg administered orally to humans produced no sedation or disorientation whatsoever. However, antinociceptive properties were observed. Doses of 250 mg and 500 mg given orally simultaneously reduced the morphine requirement for pain relief after major knee surgery and at the same time improved the pain relief, i.e. greater pain relief was reported by these patients taking alphadolone whilst they were using less morphine. None of these doses of alphadolone produced overt sedation, thus showing the potential of this drug as an analgesic without altering conscious level. It also supports the notion of the usefulness of a combination of alphadolone with an opioid.
The patients who had alphadolone administered orally to them, had blood samples taken at time 0, the time of drug administration, and at xc2xd hour intervals for 6 hours This blood was sent off to a laboratory at the Royal Melbourne Institute of Technology for analysis of blood alphadolone levels. It can be seen from Example 5 that no measurable alphadolone was found in the blood of these patients who were reporting useful analgesia with decreased morphine requirements. However, when the blood was treated with an enzyme which removes the glucuronide moiety from molecules, there was revealed the presence of alphadolone. These experiments mean that very little or no free alphadolone was present in these patient""s blood, but large quantities of alphadolone was present as the glucuronide metabolite. This evidence supports further our claim that the analgesic effects of alphadolone and alphadolone acetate given by oral and intraperitoneal routes involves activity of metabolites in general and the glucuronide in particular.